Tobacco use and obesity account for over 45% of preventable cancer deaths. Yet, these cancer risk behaviors are resistant to long-term change, despite widespread knowledge of the risks. Even with the best treatments available, most people revert to their former practices of cigarette smoking or eating. While behavior change interventions may address the habitual nature of these behaviors, they do not tackle the disruptive brain processes that undermine sustainable behavior change. Tobacco use and obesity are associated with cognitive impairments and altered brain functions that can interfere with the maintenance of goal-directed behaviors. More specifically, work in my laboratory points to the central role of alterations in working memory-related activation in the dorsolateral prefrontal cortices (DLPFC). DLPFC is at the core of the brain's cognitive control network, which supports planning, decision- making, and cognitive (self) control. Importantly, our pilot data show that DLPFC function can be safely restored using a novel and low-cost neuroscience-based intervention. Thus, the bold premise of this application is that it is possible to enhance th brain's capacity to over-ride behavioral habits that contribute to obesity and cigarette smoking, and ultimately to cancer. Broad Plan: Extending our pilot work, the proposed 7-year research plan begins with a Proof of Mechanism experiment to validate the effects of DLPFC-targeted transcranial direct current brain stimulation (tDCS) with cognitive training. Progressing to the Proof of Principle stage, experiments will identify the optimal type of cognitive training to complement tDCS and the optimal number of treatment sessions, with a focus on intermediate endpoints (e.g., cognitive function, risky decision-making, self-reported behaviors). In the final stage of the research plan, Phase II randomized controlled clinical trials will evaluate the efficacy of the optimized neuroscience-based interventions for individuals seeking treatment for smoking cessation (Study 1) and weight loss (Study 2). The deliverables are efficacious neuroscience-based interventions to be validated in Phase III clinical trials and translated to practice for behavioral cancer prevention. Qualifications: As the Mary W. Calkins Professor of Psychiatry and Deputy Director of the Abramson Cancer Center at UPenn, I have decades of experience conducting innovative behavioral science research that bridges the fields of neuroscience, pharmacology, and genetics. I have been continuously funded by NCI since 1989, with grants totaling ~$67 million in total costs (including an NCI Provocative Question Award). With >345 peer-reviewed publications, my Google Scholar H-INDEX is 90. My service includes membership on the NCI Board of Scientific Advisors, National Human Genome Research Advisory Council, and the National Institutes on Drug Abuse Advisory Council. I am a past President of the Society for Research on Nicotine and Tobacco, and an Elected Member of the Institute of Medicine of the National Academies.